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1
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Cheng Y, Zhai Y, Yuan Y, Wang Q, Li S, Sun H. The Contributions of Thrombospondin-1 to Epilepsy Formation. Neurosci Bull 2024; 40:658-672. [PMID: 38528256 PMCID: PMC11127911 DOI: 10.1007/s12264-024-01194-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 01/27/2024] [Indexed: 03/27/2024] Open
Abstract
Epilepsy is a neural network disorder caused by uncontrolled neuronal hyperexcitability induced by an imbalance between excitatory and inhibitory networks. Abnormal synaptogenesis plays a vital role in the formation of overexcited networks. Recent evidence has confirmed that thrombospondin-1 (TSP-1), mainly secreted by astrocytes, is a critical cytokine that regulates synaptogenesis during epileptogenesis. Furthermore, numerous studies have reported that TSP-1 is also involved in other processes, such as angiogenesis, neuroinflammation, and regulation of Ca2+ homeostasis, which are closely associated with the occurrence and development of epilepsy. In this review, we summarize the potential contributions of TSP-1 to epilepsy development.
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Affiliation(s)
- Yao Cheng
- School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, 264003, China
| | - Yujie Zhai
- School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, 264003, China
| | - Yi Yuan
- School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, 264003, China
| | - Qiaoyun Wang
- School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, 264003, China
| | - Shucui Li
- School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, 264003, China.
| | - Hongliu Sun
- School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, 264003, China.
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2
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Yousafzai NA, El Khalki L, Wang W, Szpendyk J, Sossey-Alaoui K. Advances in 3D Culture Models to Study Exosomes in Triple-Negative Breast Cancer. Cancers (Basel) 2024; 16:883. [PMID: 38473244 PMCID: PMC10931050 DOI: 10.3390/cancers16050883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 02/14/2024] [Accepted: 02/16/2024] [Indexed: 03/14/2024] Open
Abstract
Breast cancer, a leading cause of cancer-related deaths globally, exhibits distinct subtypes with varying pathological, genetic, and clinical characteristics. Despite advancements in breast cancer treatments, its histological and molecular heterogeneity pose a significant clinical challenge. Triple-negative breast cancer (TNBC), a highly aggressive subtype lacking targeted therapeutics, adds to the complexity of breast cancer treatment. Recent years have witnessed the development of advanced 3D culture technologies, such as organoids and spheroids, providing more representative models of healthy human tissue and various malignancies. These structures, resembling organs in structure and function, are generated from stem cells or organ-specific progenitor cells via self-organizing processes. Notably, 3D culture systems bridge the gap between 2D cultures and in vivo studies, offering a more accurate representation of in vivo tumors' characteristics. Exosomes, small nano-sized molecules secreted by breast cancer and stromal/cancer-associated fibroblast cells, have garnered significant attention. They play a crucial role in cell-to-cell communication, influencing tumor progression, invasion, and metastasis. The 3D culture environment enhances exosome efficiency compared to traditional 2D cultures, impacting the transfer of specific cargoes and therapeutic effects. Furthermore, 3D exosomes have shown promise in improving therapeutic outcomes, acting as potential vehicles for cancer treatment administration. Studies have demonstrated their role in pro-angiogenesis and their innate therapeutic potential in mimicking cellular therapies without side effects. The 3D exosome model holds potential for addressing challenges associated with drug resistance, offering insights into the mechanisms underlying multidrug resistance and serving as a platform for drug screening. This review seeks to emphasize the crucial role of 3D culture systems in studying breast cancer, especially in understanding the involvement of exosomes in cancer pathology.
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Affiliation(s)
- Neelum Aziz Yousafzai
- MetroHealth System, Cleveland, OH 44109, USA; (N.A.Y.); (L.E.K.); (W.W.)
- Department of Medicine, Case Western Reserve University, Cleveland, OH 44106-4909, USA
- Case Comprehensive Cancer Center, Cleveland, OH 44106-7285, USA
| | - Lamyae El Khalki
- MetroHealth System, Cleveland, OH 44109, USA; (N.A.Y.); (L.E.K.); (W.W.)
- Department of Medicine, Case Western Reserve University, Cleveland, OH 44106-4909, USA
- Case Comprehensive Cancer Center, Cleveland, OH 44106-7285, USA
| | - Wei Wang
- MetroHealth System, Cleveland, OH 44109, USA; (N.A.Y.); (L.E.K.); (W.W.)
- Case Comprehensive Cancer Center, Cleveland, OH 44106-7285, USA
| | - Justin Szpendyk
- MetroHealth System, Cleveland, OH 44109, USA; (N.A.Y.); (L.E.K.); (W.W.)
| | - Khalid Sossey-Alaoui
- MetroHealth System, Cleveland, OH 44109, USA; (N.A.Y.); (L.E.K.); (W.W.)
- Department of Medicine, Case Western Reserve University, Cleveland, OH 44106-4909, USA
- Case Comprehensive Cancer Center, Cleveland, OH 44106-7285, USA
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3
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Huang T, Lu C, Zhang Y, Lin BY, Zhang ZJ, Zhu D, Wang L, Lu Y. Effect of activating cancer-associated fibroblasts biomarker TNC on immune cell infiltration and prognosis in breast cancer. Ann Med 2023; 55:2250987. [PMID: 38375814 PMCID: PMC10629425 DOI: 10.1080/07853890.2023.2250987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 08/18/2023] [Indexed: 02/21/2024] Open
Abstract
BACKGROUND Cancer-associated fibroblasts (CAFs) are the most important components of the tumor microenvironment (TME). CAFs are heterogeneous and involved in tumor tumorigenesis and drug resistance, contributing to TME remodeling and predicting clinical outcomes as prognostic factors. However, the effect of CAFs the TME and the prognosis of patients with breast cancer (BC) is not fully understood. This study investigated the correlation between CAFs-activating biomarkers immune cell infiltration and survival in patients with breast cancer. METHODS RNA sequencing data and survival information for patients with breast cancer were downloaded from The Cancer Genome Atlas (TCGA) using R software. We then analyzed the correlation between CAFs-expressing biomarkers and immune cells using the clusterProfiler package, and evaluated the prognostic role of appealing genes using the Survminer package. Immunohistochemical (IHC) staining was used to determine the expression levels of TNC in 160 breast cancer samples pathologically diagnosed as invasive ductal carcinoma that were not otherwise specified (IDC-NOS). RESULTS Data analysis showed that CAFs-expressing genes was higher than in normal tissues (p < 0.05). Pathway enrichment revealed that the overexpression of CAFs-related genes was mainly enriched in the focal adhesion and phosphoinositol-3 kinase-serine/threonine kinase (PI3K-AKT) signaling pathways. Immune infiltration analysis suggested that high expression of CAFs-related genes was significantly positively correlated with the infiltration of naive B cells and resting dendritic cells and inversely correlated with macrophages cell infiltration. In addition, high TNC expression in tumor cells was associated with the most adverse clinicopathological features and reduced metastasis-free survival (MFS) (hazard ratio (HR) 0.574, 95% confidence interval (CI) 0.404-0.815, p = 0.035). CONCLUSIONS This study found that CAFs may participate in immunosuppression and regulate tumor cell proliferation and invasion. High TNC expression is associated with several adverse clinicopathological features, and high TNC expression in tumor cells has been identified as an independent prognostic factor for IDC-NOS.
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Affiliation(s)
- Ting Huang
- Department of Clinical Pathology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Cheng Lu
- The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Ying Zhang
- Department of Oncology, First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Bi-yun Lin
- Biotissue Repository, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Zhe-jun Zhang
- Department of Clinical Pathology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Di Zhu
- Department of Clinical Pathology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Liang Wang
- Department of Oncology, First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yuanzhi Lu
- Department of Clinical Pathology, The First Affiliated Hospital of Jinan University, Guangzhou, China
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4
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Berna-Erro A, Granados MP, Rosado JA, Redondo PC. Thrombotic Alterations under Perinatal Hypoxic Conditions: HIF and Other Hypoxic Markers. Int J Mol Sci 2023; 24:14541. [PMID: 37833987 PMCID: PMC10572648 DOI: 10.3390/ijms241914541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/07/2023] [Accepted: 09/08/2023] [Indexed: 10/15/2023] Open
Abstract
Hypoxia is considered to be a stressful physiological condition, which may occur during labor and the later stages of pregnancy as a result of, among other reasons, an aged placenta. Therefore, when gestation or labor is prolonged, low oxygen supply to the tissues may last for minutes, and newborns may present breathing problems and may require resuscitation maneuvers. As a result, poor oxygen supply to tissues and to circulating cells may last for longer periods of time, leading to life-threatening conditions. In contrast to the well-known platelet activation that occurs after reperfusion of the tissues due to an ischemia/reperfusion episode, platelet alterations in response to reduced oxygen exposition following labor have been less frequently investigated. Newborns overcome temporal hypoxic conditions by changing their organ functions or by adaptation of the intracellular molecular pathways. In the present review, we aim to analyze the main platelet modifications that appear at the protein level during hypoxia in order to highlight new platelet markers linked to complications arising from temporal hypoxic conditions during labor. Thus, we demonstrate that hypoxia modifies the expression and activity of hypoxic-response proteins (HRPs), including hypoxia-induced factor (HIF-1), endoplasmic reticulum oxidase 1 (Ero1), and carbonic anhydrase (CIX). Finally, we provide updates on research related to the regulation of platelet function due to HRP activation, as well as the role of HRPs in intracellular Ca2+ homeostasis.
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Affiliation(s)
- Alejandro Berna-Erro
- Department of Physiology (Phycell), University of Extremadura, Avd de la Universidad s/n, 10003 Caceres, Spain; (A.B.-E.); (P.C.R.)
| | | | - Juan Antonio Rosado
- Department of Physiology (Phycell), University of Extremadura, Avd de la Universidad s/n, 10003 Caceres, Spain; (A.B.-E.); (P.C.R.)
| | - Pedro Cosme Redondo
- Department of Physiology (Phycell), University of Extremadura, Avd de la Universidad s/n, 10003 Caceres, Spain; (A.B.-E.); (P.C.R.)
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Kim K, Huang H, Parida PK, He L, Marquez-Palencia M, Reese TC, Kapur P, Brugarolas J, Brekken RA, Malladi S. Cell Competition Shapes Metastatic Latency and Relapse. Cancer Discov 2023; 13:85-97. [PMID: 36098678 PMCID: PMC9839468 DOI: 10.1158/2159-8290.cd-22-0236] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 07/21/2022] [Accepted: 09/06/2022] [Indexed: 01/17/2023]
Abstract
Cell competition, a fitness-sensing process, is essential for tissue homeostasis. Using cancer metastatic latency models, we show that cell competition results in the displacement of latent metastatic (Lat-M) cells from the primary tumor. Lat-M cells resist anoikis and survive as residual metastatic disease. A memodeled extracellular matrix facilitates Lat-M cell displacement and survival in circulation. Disrupting cell competition dynamics by depleting secreted protein and rich in cysteine (SPARC) reduced displacement from orthotopic tumors and attenuated metastases. In contrast, depletion of SPARC after extravasation in lung-resident Lat-M cells increased metastatic outgrowth. Furthermore, multiregional transcriptomic analyses of matched primary tumors and metachronous metastases from patients with kidney cancer identified tumor subclones with Lat-M traits. Kidney cancer enriched for these Lat-M traits had a rapid onset of metachronous metastases and significantly reduced disease-free survival. Thus, an unexpected consequence of cell competition is the displacement of cells with Lat-M potential, thereby shaping metastatic latency and relapse. SIGNIFICANCE We demonstrate that cell competition within the primary tumor results in the displacement of Lat-M cells. We further show the impact of altering cell competition dynamics on metastatic incidence that may guide strategies to limit metastatic recurrences. This article is highlighted in the In This Issue feature, p. 1.
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Affiliation(s)
- Kangsan Kim
- Department of Pathology, UT Southwestern Medical Center, Dallas, Texas.,Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas
| | - Huocong Huang
- Hamon Center for Therapeutic Oncology Research and Department of Surgery, UT Southwestern Medical Center, Dallas, Texas
| | - Pravat Kumar Parida
- Department of Pathology, UT Southwestern Medical Center, Dallas, Texas.,Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas
| | - Lan He
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Mauricio Marquez-Palencia
- Department of Pathology, UT Southwestern Medical Center, Dallas, Texas.,Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas
| | - Tanner C Reese
- Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.,Department of Urology, UT Southwestern Medical Center, Dallas, Texas
| | - Payal Kapur
- Department of Pathology, UT Southwestern Medical Center, Dallas, Texas.,Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.,Kidney Cancer Program, UT Southwestern Medical Center, Dallas, Texas
| | - James Brugarolas
- Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.,Kidney Cancer Program, UT Southwestern Medical Center, Dallas, Texas.,Hematology-Oncology Division, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas
| | - Rolf A Brekken
- Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.,Hamon Center for Therapeutic Oncology Research and Department of Surgery, UT Southwestern Medical Center, Dallas, Texas
| | - Srinivas Malladi
- Department of Pathology, UT Southwestern Medical Center, Dallas, Texas.,Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas
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SPARC Induces E-Cadherin Repression and Enhances Cell Migration through Integrin αvβ3 and the Transcription Factor ZEB1 in Prostate Cancer Cells. Int J Mol Sci 2022; 23:ijms23115874. [PMID: 35682554 PMCID: PMC9180154 DOI: 10.3390/ijms23115874] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 05/11/2022] [Accepted: 05/18/2022] [Indexed: 02/06/2023] Open
Abstract
Secreted protein acidic and rich in cysteine (SPARC), or osteonectin, is a matricellular protein that modulates interactions between cells and their microenvironment. SPARC is expressed during extracellular matrix remodeling and is abundant in bone marrow and high-grade prostate cancer (PCa). In PCa, SPARC induces changes associated with epithelial–mesenchymal transition (EMT), enhancing migration and invasion and increasing the expression of EMT transcriptional factor Zinc finger E-box-binding homeobox 1 (ZEB1), but not Zinc finger protein SNAI1 (Snail) or Zinc finger protein SNAI2 (Slug). It is unknown whether the SPARC-induced downregulation of E-cadherin in PCa cells depends on ZEB1. Several integrins are mediators of SPARC effects in cancer cells. Because integrin signaling can induce EMT programs, we hypothesize that SPARC induces E-cadherin repression through the activation of integrins and ZEB1. Through stable knockdown and the overexpression of SPARC in PCa cells, we demonstrate that SPARC downregulates E-cadherin and increases vimentin, ZEB1, and integrin β3 expression. Knocking down SPARC in PCa cells decreases the tyrosine-925 phosphorylation of FAK and impairs focal adhesion formation. Blocking integrin αvβ3 and silencing ZEB1 revert both the SPARC-induced downregulation of E-cadherin and cell migration enhancement. We conclude that SPARC induces E-cadherin repression and enhances PCa cell migration through the integrin αvβ3/ZEB1 signaling pathway.
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Gopinath P, Natarajan A, Sathyanarayanan A, Veluswami S, Gopisetty G. The multifaceted role of Matricellular Proteins in health and cancer, as biomarkers and therapeutic targets. Gene 2022; 815:146137. [PMID: 35007686 DOI: 10.1016/j.gene.2021.146137] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 12/07/2021] [Accepted: 12/20/2021] [Indexed: 02/07/2023]
Abstract
The extracellular matrix (ECM) is composed of a mesh of proteins, proteoglycans, growth factors, and other secretory components. It constitutes the tumor microenvironment along with the endothelial cells, cancer-associated fibroblasts, adipocytes, and immune cells. The proteins of ECM can be functionally classified as adhesive proteins and matricellular proteins (MCP). In the tumor milieu, the ECM plays a major role in tumorigenesis and therapeutic resistance. The current review encompasses thrombospondins, osteonectin, osteopontin, tenascin C, periostin, the CCN family, laminin, biglycan, decorin, mimecan, and galectins. The matrix metalloproteinases (MMPs) are also discussed as they are an integral part of the ECM with versatile functions in the tumor stroma. In this review, the role of these proteins in tumor initiation, growth, invasion and metastasis have been highlighted, with emphasis on their contribution to tumor therapeutic resistance. Further, their potential as biomarkers and therapeutic targets based on existing evidence are discussed. Owing to the recent advancements in protein targeting, the possibility of agents to modulate MCPs in cancer as therapeutic options are discussed.
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Affiliation(s)
- Prarthana Gopinath
- Department of Molecular Oncology, Cancer Institute WIA, Chennai, Tamil Nadu, India
| | - Aparna Natarajan
- Department of Molecular Oncology, Cancer Institute WIA, Chennai, Tamil Nadu, India
| | | | - Sridevi Veluswami
- Deaprtment of Surgical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
| | - Gopal Gopisetty
- Department of Molecular Oncology, Cancer Institute WIA, Chennai, Tamil Nadu, India.
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8
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Okada T, Suzuki H, Travis ZD, Altay O, Tang J, Zhang JH. SPARC Aggravates Blood-Brain Barrier Disruption via Integrin αV β3/MAPKs/MMP-9 Signaling Pathway after Subarachnoid Hemorrhage. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:9739977. [PMID: 34804372 PMCID: PMC8601826 DOI: 10.1155/2021/9739977] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/18/2021] [Indexed: 01/17/2023]
Abstract
Blood-brain barrier (BBB) disruption is a common and critical pathology following subarachnoid hemorrhage (SAH). We investigated the BBB disruption property of secreted protein acidic and rich in cysteine (SPARC) after SAH. A total of 197 rats underwent endovascular perforation to induce SAH or sham operation. Small interfering ribonucleic acid (siRNA) for SPARC or scrambled siRNA was administered intracerebroventricularly to rats 48 h before SAH. Anti-SPARC monoclonal antibody (mAb) 236 for functional blocking or normal mouse immunoglobulin G (IgG) was administered intracerebroventricularly 1 h after SAH. Selective integrin αVβ3 inhibitor cyclo(-RGDfK) or phosphate-buffered saline was administered intranasally 1 h before SAH, along with recombinant SPARC treatment. Neurobehavior, SAH severity, brain edema, immunohistochemical staining, and Western blot were evaluated. The expression of SPARC and integrin αVβ3 was upregulated after SAH in the endothelial cells. SPARC siRNA and anti-SPARC mAb 236 prevented neuroimpairments and brain edema through protection of BBB as measured by IgG extravasation 24 and 72 h after SAH. Recombinant SPARC aggravated neuroimpairments and cyclo(-RGDfK) suppressed the harmful neurological effects via inhibition of activated c-Jun N-terminal kinase, p38, and matrix metalloproteinase-9 followed by retention of endothelial junction proteins. SPARC may induce post-SAH BBB disruption via integrin αVβ3 signaling pathway.
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Affiliation(s)
- Takeshi Okada
- Department of Neurosurgery, Kuwana City Medical Center, 3-11 Kotobuki-cho, Kuwana, Mie 511-0061, Japan
- Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan
- Department of Physiology and Pharmacology, Loma Linda University, Risley Hall, Room 219, 11041 Campus St., Loma Linda, CA 92354, USA
| | - Hidenori Suzuki
- Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan
| | - Zachary D. Travis
- Department of Physiology and Pharmacology, Loma Linda University, Risley Hall, Room 219, 11041 Campus St., Loma Linda, CA 92354, USA
- Department of Earth and Biological Sciences, Loma Linda University, Risley Hall, Room 219, 11041 Campus St., Loma Linda, CA 92354, USA
| | - Orhan Altay
- Department of Physiology and Pharmacology, Loma Linda University, Risley Hall, Room 219, 11041 Campus St., Loma Linda, CA 92354, USA
| | - Jiping Tang
- Department of Physiology and Pharmacology, Loma Linda University, Risley Hall, Room 219, 11041 Campus St., Loma Linda, CA 92354, USA
| | - John H. Zhang
- Department of Physiology and Pharmacology, Loma Linda University, Risley Hall, Room 219, 11041 Campus St., Loma Linda, CA 92354, USA
- Department of Anesthesiology, Loma Linda University, Risley Hall, Room 219, 11041 Campus St., Loma Linda, CA 92354, USA
- Department of Neurosurgery, Loma Linda University, Risley Hall, Room 219, 11041 Campus St., Loma Linda, CA 92354, USA
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9
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The role of extracellular matrix in tumour angiogenesis: the throne has NOx servants. Biochem Soc Trans 2021; 48:2539-2555. [PMID: 33150941 PMCID: PMC7752075 DOI: 10.1042/bst20200208] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 09/28/2020] [Accepted: 10/05/2020] [Indexed: 02/07/2023]
Abstract
The extracellular matrix (ECM) dynamics in tumour tissue are deregulated compared to the ECM in healthy tissue along with disorganized architecture and irregular behaviour of the residing cells. Nitric oxide (NO) as a pleiotropic molecule exerts different effects on the components of the ECM driving or inhibiting augmented angiogenesis and tumour progression and tumour cell proliferation and metastasis. These effects rely on the concentration of NO within the tumour tissue, the nature of the surrounding microenvironment and the sensitivity of resident cells to NO. In this review article, we summarize the recent findings on the correlation between the levels of NO and the ECM components towards the modulation of tumour angiogenesis in different types of cancers. These are discussed principally in the context of how NO modulates the expression of ECM proteins resulting in either the promotion or inhibition of tumour growth via tumour angiogenesis. Furthermore, the regulatory effects of individual ECM components on the expression of the NO synthase enzymes and NO production were reviewed. These findings support the current efforts for developing effective therapeutics for cancers.
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10
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Ray SK, Mukherjee S. Consequences of Extracellular Matrix Remodeling in Headway and Metastasis of Cancer along with Novel Immunotherapies: A Great Promise for Future Endeavor. Anticancer Agents Med Chem 2021; 22:1257-1271. [PMID: 34254930 DOI: 10.2174/1871520621666210712090017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 05/23/2021] [Accepted: 05/30/2021] [Indexed: 12/12/2022]
Abstract
Tissues are progressively molded by bidirectional correspondence between denizen cells and extracellular matrix (ECM) via cell-matrix connections along with ECM remodeling. The composition and association of ECM are spatiotemporally directed to control cell conduct and differentiation; however, dysregulation of ECM dynamics prompts the development of diseases, for example, cancer. Emerging information demonstrates that hypoxia may have decisive roles in metastasis. In addition, the sprawling nature of neoplastic cells and chaotic angiogenesis are increasingly influencing microcirculation as well as altering the concentration of oxygen. In various regions of the tumor microenvironment, hypoxia, an essential player in the multistep phase of cancer metastasis, is necessary. Hypoxia can be turned into an advantage for selective cancer therapy because it is much more severe in tumors than in normal tissues. Cellular matrix gives signaling cues that control cell behavior and organize cells' elements in tissue development and homeostasis. The interplay between intrinsic factors of cancer cells themselves, including their genotype and signaling networks, and extrinsic factors of tumor stroma, for example, ECM and ECM remodeling, together decide the destiny and behavior of tumor cells. Tumor matrix encourages the development, endurance, and invasion of neoplastic and immune cell activities to drive metastasis and debilitate treatment. Incipient evidence recommends essential parts of tumor ECM segments and their remodeling in controlling each progression of the cancer-immunity cycle. Scientists have discovered that tumor matrix dynamics as well as matrix remodeling in perspective to anti-tumor immune reactions are especially important for matrix-based biomarkers recognition and followed by immunotherapy and targeting specific drugs.
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Affiliation(s)
- Suman Kumar Ray
- Department of Applied Sciences, Indira Gandhi Technological and Medical Sciences University, India
| | - Sukhes Mukherjee
- Department of Biochemistry. All India Institute of Medical Sciences Bhopal, Madhya pradesh-462020, India
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11
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CCN proteins in the musculoskeletal system: current understanding and challenges in physiology and pathology. J Cell Commun Signal 2021; 15:545-566. [PMID: 34228239 PMCID: PMC8642527 DOI: 10.1007/s12079-021-00631-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 06/14/2021] [Indexed: 02/07/2023] Open
Abstract
The acronym for the CCN family was recently revised to represent “cellular communication network”. These six, small, cysteine-enriched and evolutionarily conserved proteins are secreted matricellular proteins, that convey and modulate intercellular communication by interacting with structural proteins, signalling factors and cell surface receptors. Their role in the development and physiology of musculoskeletal system, constituted by connective tissues where cells are interspersed in the cellular matrix, has been broadly studied. Previous research has highlighted a crucial balance of CCN proteins in mesenchymal stem cell commitment and a pivotal role for CCN1, CCN2 and their alter ego CCN3 in chondrogenesis and osteogenesis; CCN4 plays a minor role and the role of CCN5 and CCN6 is still unclear. CCN proteins also participate in osteoclastogenesis and myogenesis. In adult life, CCN proteins serve as mechanosensory proteins in the musculoskeletal system providing a steady response to environmental stimuli and participating in fracture healing. Substantial evidence also supports the involvement of CCN proteins in inflammatory pathologies, such as osteoarthritis and rheumatoid arthritis, as well as in cancers affecting the musculoskeletal system and bone metastasis. These matricellular proteins indeed show involvement in inflammation and cancer, thus representing intriguing therapeutic targets. This review discusses the current understanding of CCN proteins in the musculoskeletal system as well as the controversies and challenges associated with their multiple and complex roles, and it aims to link the dispersed knowledge in an effort to stimulate and guide readers to an area that the writers consider to have significant impact and relevant potentialities.
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12
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Okada T, Suzuki H. The Role of Tenascin-C in Tissue Injury and Repair After Stroke. Front Immunol 2021; 11:607587. [PMID: 33552066 PMCID: PMC7859104 DOI: 10.3389/fimmu.2020.607587] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 12/04/2020] [Indexed: 12/16/2022] Open
Abstract
Stroke is still one of the most common causes for mortality and morbidity worldwide. Following acute stroke onset, biochemical and cellular changes induce further brain injury such as neuroinflammation, cell death, and blood-brain barrier disruption. Matricellular proteins are non-structural proteins induced by many stimuli and tissue damage including stroke induction, while its levels are generally low in a normal physiological condition in adult tissues. Currently, a matricellular protein tenascin-C (TNC) is considered to be an important inducer to promote neuroinflammatory cascades and the resultant pathology in stroke. TNC is upregulated in cerebral arteries and brain tissues including astrocytes, neurons, and brain capillary endothelial cells following subarachnoid hemorrhage (SAH). TNC may be involved in blood-brain barrier disruption, neuronal apoptosis, and cerebral vasospasm via the activation of mitogen-activated protein kinases and nuclear factor-kappa B following SAH. In addition, post-SAH TNC levels in cerebrospinal fluid predicted the development of delayed cerebral ischemia and angiographic vasospasm in clinical settings. On the other hand, TNC is reported to promote fibrosis and exert repair effects for an experimental aneurysm via macrophages-induced migration and proliferation of smooth muscle cells. The authors review TNC-induced inflammatory signal cascades and the relationships with other matricellular proteins in stroke-related pathology.
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Affiliation(s)
- Takeshi Okada
- Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Japan.,Department of Neurosurgery, Kuwana City Medical Center, Kuwana, Japan
| | - Hidenori Suzuki
- Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Japan
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13
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Stromal Protein-Mediated Immune Regulation in Digestive Cancers. Cancers (Basel) 2021; 13:cancers13010146. [PMID: 33466303 PMCID: PMC7795083 DOI: 10.3390/cancers13010146] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/21/2020] [Accepted: 12/24/2020] [Indexed: 12/13/2022] Open
Abstract
Simple Summary Solid cancers are surrounded by a network of non-cancerous cells comprising different cell types, including fibroblasts, and acellular protein structures. This entire network is called the tumor microenvironment (TME) and it provides a physical barrier to the tumor shielding it from infiltrating immune cells, such as lymphocytes, or therapeutic agents. In addition, the TME has been shown to dampen efficient immune responses of infiltrated immune cells, which are key in eliminating cancer cells from the organism. In this review, we will discuss how TME proteins in particular are involved in this dampening effect, known as immunosuppression. We will focus on three different types of digestive cancers: pancreatic cancer, colorectal cancer, and gastric cancer. Moreover, we will discuss current therapeutic approaches using TME proteins as targets to reverse their immunosuppressive effects. Abstract The stromal tumor microenvironment (TME) consists of immune cells, vascular and neural structures, cancer-associated fibroblasts (CAFs), as well as extracellular matrix (ECM), and favors immune escape mechanisms promoting the initiation and progression of digestive cancers. Numerous ECM proteins released by stromal and tumor cells are crucial in providing physical rigidity to the TME, though they are also key regulators of the immune response against cancer cells by interacting directly with immune cells or engaging with immune regulatory molecules. Here, we discuss current knowledge of stromal proteins in digestive cancers including pancreatic cancer, colorectal cancer, and gastric cancer, focusing on their functions in inhibiting tumor immunity and enabling drug resistance. Moreover, we will discuss the implication of stromal proteins as therapeutic targets to unleash efficient immunotherapy-based treatments.
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14
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Fiorino S, Visani M, Masetti M, Acquaviva G, Tallini G, De Leo A, Fornelli A, Ragazzi M, Vasuri F, Grifoni D, Argento CM, Maloberti T, Ravaioli M, Fabbri C, Jovine E, Pession A, de Biase D. Periostin, tenascin, osteopontin isoforms in long- and non-long survival patients with pancreatic cancer: a pilot study. Mol Biol Rep 2020; 47:8235-8241. [PMID: 32886326 DOI: 10.1007/s11033-020-05763-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Accepted: 08/28/2020] [Indexed: 02/05/2023]
Abstract
Pancreatic adenocarcinoma (PDAC) is the most frequent histological type of malignancy in the pancreas. Extracellular matrix (ECM), plays a critical role during the process of human carcinogenesis and the possible diversity in matricellular proteins composition of ECM may have a significant impact on the clinical course of PDAC. Aim of this paper was to evaluate the expression of three matricellular proteins, including Periostin (POSTN), Tenascin (TNS) and Osteopontin (OPN), in PDAC from long-survival (LS) and non-long survival (NLS) patients. A total of 30 PDAC were analyzed, 15 from patients that survived more than 60 months after surgery (LS) and 15 that died from the disease within 24 (NLS). RNA was extracted and OPN, TNS and POSTN mRNA levels were evaluated by qRT-PCR. LS and NLS samples showed the same type of POSTN and TN isoforms. On the contrary, OPN seems to be preferentially expressed in NLS PDAC. Moreover, OPNb and OPNc isoforms were expressed exclusively in NLS samples. In conclusion, Our data led to hypothesize a possible relationship between the expression of different isoforms of each of these proteins and the clinical outcome of patients with PDAC.
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Affiliation(s)
- Sirio Fiorino
- Internal Medicine Unit, Budrio Hospital, Azienda USL Bologna, Bologna, Italy.
| | - Michela Visani
- Department of Medicine, Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale)-Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna School of Medicine, Bologna, Italy
- Department of Pharmacy and Biotechnology, Dipartimento di Farmacia e Biotecnologie)-Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna, Viale Ercolani 4/2, 40139, Bologna, Italy
| | | | - Giorgia Acquaviva
- Department of Medicine, Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale)-Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna School of Medicine, Bologna, Italy
| | - Giovanni Tallini
- Department of Medicine, Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale)-Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna School of Medicine, Bologna, Italy
| | - Antonio De Leo
- Department of Medicine, Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale)-Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna School of Medicine, Bologna, Italy
| | - Adele Fornelli
- Anatomic Pathology Unit, Azienda USL-Maggiore Hospital, Bologna, Italy
| | - Moira Ragazzi
- Anatomic Pathology Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy
| | - Francesco Vasuri
- Anatomic Pathology Unit, "F. Addarii" Institute of Oncology and Transplantation Pathology, S. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Daniela Grifoni
- Department of Pharmacy and Biotechnology, Dipartimento di Farmacia e Biotecnologie)-Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna, Viale Ercolani 4/2, 40139, Bologna, Italy
| | - Chiara Maria Argento
- Department of Pharmacy and Biotechnology, Dipartimento di Farmacia e Biotecnologie)-Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna, Viale Ercolani 4/2, 40139, Bologna, Italy
| | - Thais Maloberti
- Department of Pharmacy and Biotechnology, Dipartimento di Farmacia e Biotecnologie)-Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna, Viale Ercolani 4/2, 40139, Bologna, Italy
| | - Matteo Ravaioli
- Department of General Surgery and Transplantation, St. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Carlo Fabbri
- Unit of Gastroenterology and Digestive Endoscopy, Forlì-Cesena Hospital, Forlì-Cesena, Italy
| | - Elio Jovine
- Surgery Unit, Azienda USL-Maggiore Hospital, Bologna, Italy
| | - Annalisa Pession
- Department of Pharmacy and Biotechnology, Dipartimento di Farmacia e Biotecnologie)-Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna, Viale Ercolani 4/2, 40139, Bologna, Italy
| | - Dario de Biase
- Department of Pharmacy and Biotechnology, Dipartimento di Farmacia e Biotecnologie)-Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna, Viale Ercolani 4/2, 40139, Bologna, Italy.
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15
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Sala M, Ros M, Saltel F. A Complex and Evolutive Character: Two Face Aspects of ECM in Tumor Progression. Front Oncol 2020; 10:1620. [PMID: 32984031 PMCID: PMC7485352 DOI: 10.3389/fonc.2020.01620] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 07/27/2020] [Indexed: 12/24/2022] Open
Abstract
Tumor microenvironment, including extracellular matrix (ECM) and stromal cells, is a key player during tumor development, from initiation, growth and progression to metastasis. During all of these steps, remodeling of matrix components occurs, changing its biochemical and physical properties. The global and basic cancer ECM model is that tumors are surrounded by activated stromal cells, that remodel physiological ECM to evolve into a stiffer and more crosslinked ECM than in normal conditions, thereby increasing invasive capacities of cancer cells. In this review, we show that this too simple model does not consider the complexity, specificity and heterogeneity of each organ and tumor. First, we describe the general ECM in context of cancer. Then, we go through five invasive and most frequent cancers from different origins (breast, liver, pancreas, colon, and skin), and show that each cancer has its own specific matrix, with different stromal cells, ECM components, biochemical properties and activated signaling pathways. Furthermore, in these five cancers, we describe the dual role of tumor ECM: as a protective barrier against tumor cell proliferation and invasion, and as a major player in tumor progression. Indeed, crosstalk between tumor and stromal cells induce changes in matrix organization by remodeling ECM through invadosome formation in order to degrade it, promoting tumor progression and cell invasion. To sum up, in this review, we highlight the specificities of matrix composition in five cancers and the necessity not to consider the ECM as one general and simple entity, but one complex, dynamic and specific entity for each cancer type and subtype.
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16
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López-Moncada F, Torres MJ, Castellón EA, Contreras HR. Secreted protein acidic and rich in cysteine (SPARC) induces epithelial-mesenchymal transition, enhancing migration and invasion, and is associated with high Gleason score in prostate cancer. Asian J Androl 2020; 21:557-564. [PMID: 31031331 PMCID: PMC6859668 DOI: 10.4103/aja.aja_23_19] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein highly expressed in bone tissue that acts as a chemoattractant factor promoting the arrival of prostate cancer (PCa) cells to the bone marrow. However, the contribution of SPARC during the early stages of tumor progression remains unclear. In this study, we show that SPARC is highly expressed in PCa tissues with a higher Gleason score. Through stable knockdown and overexpression of SPARC in PC3 and LNCaP cells, respectively, here we demonstrate that endogenous SPARC induces the epithelial-mesenchymal transition (EMT), decreasing E-cadherin and cytokeratin 18 and increasing N-cadherin and vimentin. Moreover, SPARC induces the expression of EMT regulatory transcription factors Snail family transcriptional repressor 1 (Snail), Snail family transcriptional repressor 2 (Slug), and zinc finger E-box binding homeobox 1 (Zeb1). In addition, SPARC knockdown in PC3 cells decreases migration and invasion in vitro, without modifying cell proliferation. Our results indicate that SPARC might facilitate tumor progression by modifying the cellular phenotype in cancer cells.
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Affiliation(s)
- Fernanda López-Moncada
- Department of Basic and Clinic Oncology, Faculty of Medicine, University of Chile, Santiago 8389100, Chile
| | - María José Torres
- Department of Basic and Clinic Oncology, Faculty of Medicine, University of Chile, Santiago 8389100, Chile
| | - Enrique A Castellón
- Department of Basic and Clinic Oncology, Faculty of Medicine, University of Chile, Santiago 8389100, Chile
| | - Héctor R Contreras
- Department of Basic and Clinic Oncology, Faculty of Medicine, University of Chile, Santiago 8389100, Chile
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17
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Gerarduzzi C, Hartmann U, Leask A, Drobetsky E. The Matrix Revolution: Matricellular Proteins and Restructuring of the Cancer Microenvironment. Cancer Res 2020; 80:2705-2717. [PMID: 32193287 DOI: 10.1158/0008-5472.can-18-2098] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Revised: 12/04/2019] [Accepted: 03/17/2020] [Indexed: 11/16/2022]
Abstract
The extracellular matrix (ECM) surrounding cells is indispensable for regulating their behavior. The dynamics of ECM signaling are tightly controlled throughout growth and development. During tissue remodeling, matricellular proteins (MCP) are secreted into the ECM. These factors do not serve classical structural roles, but rather regulate matrix proteins and cell-matrix interactions to influence normal cellular functions. In the tumor microenvironment, it is becoming increasingly clear that aberrantly expressed MCPs can support multiple hallmarks of carcinogenesis by interacting with various cellular components that are coupled to an array of downstream signals. Moreover, MCPs also reorganize the biomechanical properties of the ECM to accommodate metastasis and tumor colonization. This realization is stimulating new research on MCPs as reliable and accessible biomarkers in cancer, as well as effective and selective therapeutic targets.
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Affiliation(s)
- Casimiro Gerarduzzi
- Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada. .,Département de Médecine, Université de Montréal, Montréal, Québec, Canada
| | - Ursula Hartmann
- Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany
| | - Andrew Leask
- College of Dentistry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Elliot Drobetsky
- Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada.,Département de Médecine, Université de Montréal, Montréal, Québec, Canada
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18
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Rigoglio NN, Rabelo ACS, Borghesi J, de Sá Schiavo Matias G, Fratini P, Prazeres PHDM, Pimentel CMMM, Birbrair A, Miglino MA. The Tumor Microenvironment: Focus on Extracellular Matrix. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1245:1-38. [PMID: 32266651 DOI: 10.1007/978-3-030-40146-7_1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The extracellular matrix (ECM) regulates the development and maintains tissue homeostasis. The ECM is composed of a complex network of molecules presenting distinct biochemical properties to regulate cell growth, survival, motility, and differentiation. Among their components, proteoglycans (PGs) are considered one of the main components of ECM. Its composition, biomechanics, and anisotropy are exquisitely tuned to reflect the physiological state of the tissue. The loss of ECM's homeostasis is seen as one of the hallmarks of cancer and, typically, defines transitional events in tumor progression and metastasis. In this chapter, we discuss the types of proteoglycans and their roles in cancer. It has been observed that the amount of some ECM components is increased, while others are decreased, depending on the type of tumor. However, both conditions corroborate with tumor progression and malignancy. Therefore, ECM components have an increasingly important role in carcinogenesis and this leads us to believe that their understanding may be a key in the discovery of new anti-tumor therapies. In this book, the main ECM components will be discussed in more detail in each chapter.
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Affiliation(s)
- Nathia Nathaly Rigoglio
- Department of Surgery, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Ana Carolina Silveira Rabelo
- Department of Surgery, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Jessica Borghesi
- Department of Surgery, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Gustavo de Sá Schiavo Matias
- Department of Surgery, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Paula Fratini
- Department of Surgery, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | | | | | - Alexander Birbrair
- Department of Radiology, Columbia University Medical Center, New York, NY, USA
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Maria Angelica Miglino
- Department of Surgery, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil.
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19
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James NE, Cantillo E, Oliver MT, Rowswell-Turner RB, Ribeiro JR, Kim KK, Chichester CO, DiSilvestro PA, Moore RG, Singh RK, Yano N, Zhao TC. HE4 suppresses the expression of osteopontin in mononuclear cells and compromises their cytotoxicity against ovarian cancer cells. Clin Exp Immunol 2019; 193:327-340. [PMID: 29745428 DOI: 10.1111/cei.13153] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/03/2018] [Indexed: 12/15/2022] Open
Abstract
Ovarian cancers are known to evade immunosurveillance and to orchestrate a suppressive immune microenvironment. Here we examine the role of human epididymis protein 4 (HE4), an ovarian cancer biomarker, in immune evasion. Through modified subtractive hybridization analyses we have characterized the gene targets of HE4 in human peripheral blood mononuclear cells (PBMCs), and established a preliminary mechanism for HE4-mediated immune failure in ovarian tumours. Upon exposure of purified PMBCs to HE4, osteopontin (OPN) and dual-specificity phosphatase 6 (DUSP6) emerged as the most suppressed and up-regulated genes, respectively. SKOV3 and OVCAR8, human ovarian carcinoma cell lines, exhibited enhanced proliferation in conditioned media from HE4-exposed PBMCs, an effect that was attenuated by the addition of recombinant OPN or OPN-inducible cytokines [interleukin (IL)-12 and interferon (IFN)-Ɣ]. Additionally, upon co-culture with PBMCs, HE4-silenced SKOV3 cells were found to be more susceptible to cytotoxic cell death. The relationship between HE4 and OPN was reinforced further through the analysis of serous ovarian cancer patient samples. In these biopsy specimens, the number of OPN+ T cells correlated positively with progression free survival (PFS) and inversely with serum HE4 level. Taken together, these findings show that HE4 enhances ovarian cancer tumorigenesis by compromising OPN-mediated T cell activation.
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Affiliation(s)
- N E James
- Department of Obstetrics and Gynecology, Program in Women's Oncology, Women and Infants Hospital, The Warren Alpert Medical School of Brown University, Providence, RI, USA.,Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - E Cantillo
- Department of Obstetrics and Gynecology, Program in Women's Oncology, Women and Infants Hospital, The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - M T Oliver
- Department of Obstetrics and Gynecology, Program in Women's Oncology, Women and Infants Hospital, The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | | | - J R Ribeiro
- Department of Obstetrics and Gynecology, Program in Women's Oncology, Women and Infants Hospital, The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - K-K Kim
- Department of Pharmacy, University of Rhode Island, Kingston, RI, USA
| | - C O Chichester
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - P A DiSilvestro
- Department of Obstetrics and Gynecology, Program in Women's Oncology, Women and Infants Hospital, The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - R G Moore
- Department of Pharmacy, University of Rhode Island, Kingston, RI, USA
| | - R K Singh
- Department of Obstetrics and Gynecology, Program in Women's Oncology, Women and Infants Hospital, The Warren Alpert Medical School of Brown University, Providence, RI, USA.,Department of Pharmacy, University of Rhode Island, Kingston, RI, USA
| | - N Yano
- Department of Obstetrics and Gynecology, Program in Women's Oncology, Women and Infants Hospital, The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - T C Zhao
- Department of Surgery, Roger Williams Medical Center, Providence, RI, USA
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20
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Hong Y, Rao Y. Current status of nanoscale drug delivery systems for colorectal cancer liver metastasis. Biomed Pharmacother 2019; 114:108764. [DOI: 10.1016/j.biopha.2019.108764] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 02/25/2019] [Accepted: 03/06/2019] [Indexed: 12/24/2022] Open
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21
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Aftab Q, Mesnil M, Ojefua E, Poole A, Noordenbos J, Strale PO, Sitko C, Le C, Stoynov N, Foster LJ, Sin WC, Naus CC, Chen VC. Cx43-Associated Secretome and Interactome Reveal Synergistic Mechanisms for Glioma Migration and MMP3 Activation. Front Neurosci 2019; 13:143. [PMID: 30941001 PMCID: PMC6433981 DOI: 10.3389/fnins.2019.00143] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Accepted: 02/07/2019] [Indexed: 12/23/2022] Open
Abstract
Extracellular matrix (ECM) remodeling, degradation and glioma cell motility are critical aspects of glioblastoma multiforme (GBM). Despite being a rich source of potential biomarkers and targets for therapeutic advance, the dynamic changes occurring within the extracellular environment that are specific to GBM motility have yet to be fully resolved. The gap junction protein connexin43 (Cx43) increases glioma migration and invasion in a variety of in vitro and in vivo models. In this study, the upregulation of Cx43 in C6 glioma cells induced morphological changes and the secretion of proteins associated with cell motility. Demonstrating the selective engagement of ECM remodeling networks, secretome analysis revealed the near-binary increase of osteopontin and matrix metalloproteinase-3 (MMP3), with gelatinase and NFF-3 assays confirming the proteolytic activities. Informatic analysis of interactome and secretome downstream of Cx43 identifies networks of glioma motility that appear to be synergistically engaged. The data presented here implicate ECM remodeling and matrikine signals downstream of Cx43/MMP3/osteopontin and ARK1B10 inhibition as possible avenues to inhibit GBM.
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Affiliation(s)
- Qurratulain Aftab
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Marc Mesnil
- Signalisation et Transports Ioniques Membranaires (STIM), CNRS ERL 7003, University of Poitiers, Poitiers, France
| | - Emmanuel Ojefua
- Department of Chemistry, Brandon University, Brandon, MB, Canada
| | - Alisha Poole
- Department of Chemistry, Brandon University, Brandon, MB, Canada
| | - Jenna Noordenbos
- Department of Chemistry, Brandon University, Brandon, MB, Canada
| | - Pierre-Olivier Strale
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Chris Sitko
- Department of Chemistry, Brandon University, Brandon, MB, Canada
| | - Caitlin Le
- Department of Chemistry, Brandon University, Brandon, MB, Canada
| | - Nikolay Stoynov
- Department of Biochemistry and Molecular Biology, Centre for High-Throughput Biology, University of British Columbia, Vancouver, BC, Canada
| | - Leonard J Foster
- Department of Biochemistry and Molecular Biology, Centre for High-Throughput Biology, University of British Columbia, Vancouver, BC, Canada
| | - Wun-Chey Sin
- Signalisation et Transports Ioniques Membranaires (STIM), CNRS ERL 7003, University of Poitiers, Poitiers, France
| | - Christian C Naus
- Signalisation et Transports Ioniques Membranaires (STIM), CNRS ERL 7003, University of Poitiers, Poitiers, France
| | - Vincent C Chen
- Department of Chemistry, Brandon University, Brandon, MB, Canada
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22
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Efremov YR, Proskurina AS, Potter EA, Dolgova EV, Efremova OV, Taranov OS, Ostanin AA, Chernykh ER, Kolchanov NA, Bogachev SS. Cancer Stem Cells: Emergent Nature of Tumor Emergency. Front Genet 2018; 9:544. [PMID: 30505319 PMCID: PMC6250818 DOI: 10.3389/fgene.2018.00544] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 10/26/2018] [Indexed: 12/12/2022] Open
Abstract
A functional analysis of 167 genes overexpressed in Krebs-2 tumor initiating cells was performed. In the first part of the study, the genes were analyzed for their belonging to one or more of the three groups, which represent the three major phenotypic manifestation of malignancy of cancer cells, namely (1) proliferative self-sufficiency, (2) invasive growth and metastasis, and (3) multiple drug resistance. 96 genes out of 167 were identified as possible contributors to at least one of these fundamental properties. It was also found that substantial part of these genes are also known as genes responsible for formation and/or maintenance of the stemness of normal pluri-/multipotent stem cells. These results suggest that the malignancy is simply the ability to maintain the stem cell specific genes expression profile, and, as a consequence, the stemness itself regardless of the controlling effect of stem niches. In the second part of the study, three stress factors combined into the single concept of "generalized cellular stress," which are assumed to activate the expression of these genes, were defined. In addition, possible mechanisms for such activation were identified. The data obtained suggest the existence of a mechanism for the de novo formation of a pluripotent/stem phenotype in the subpopulation of "committed" tumor cells.
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Affiliation(s)
- Yaroslav R Efremov
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.,Department of Natural Sciences, Novosibirsk State University, Novosibirsk, Russia
| | - Anastasia S Proskurina
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - Ekaterina A Potter
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - Evgenia V Dolgova
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - Oksana V Efremova
- Department of Natural Sciences, Novosibirsk State University, Novosibirsk, Russia
| | - Oleg S Taranov
- The State Research Center of Virology and Biotechnology Vector, Koltsovo, Russia
| | - Aleksandr A Ostanin
- Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
| | - Elena R Chernykh
- Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
| | - Nikolay A Kolchanov
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - Sergey S Bogachev
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
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23
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Wang Y, Xu H, Zhu B, Qiu Z, Lin Z. Systematic identification of the key candidate genes in breast cancer stroma. Cell Mol Biol Lett 2018; 23:44. [PMID: 30237810 PMCID: PMC6142385 DOI: 10.1186/s11658-018-0110-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 08/29/2018] [Indexed: 12/14/2022] Open
Abstract
Background Tumor microenvironment, in particular the stroma, plays an important role in breast cancer cell invasion and metastasis. Investigation of the molecular characteristics of breast cancer stroma may reveal targets for future study. Methods The transcriptome profiles of breast cancer stroma and normal breast stroma were compared to identify differentially expressed genes (DEGs). The method was analysis of GSE26910 and GSE10797 datasets. Common DEGs were identified and then analyses of enriched pathways and hub genes were performed. Results A total of 146 DEGs were common to GSE26910 and GSE10797. The enriched pathways were associated with "extracellular matrix (ECM) organization", "ECM-receptor interaction" and "focal adhesion". Network analysis identified six key genes, including JUN, FOS, ATF3, STAT1, COL1A1 and FN1. Notably, COL1A1 and FN1 were identified for the first time as cancer stromal key genes associated with breast cancer invasion and metastasis. Oncome analysis showed that the high expression levels of COL1A1 and FN1 correlated to an advanced stage of breast cancer and poor clinical outcomes. Conclusions We found that several conserved tumor stromal genes might regulate breast cancer invasion through ECM remodeling. The clinical outcome analyses of COL1A1 and FN1 suggest these two genes are promising targets for future studies.
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Affiliation(s)
- Yanxia Wang
- 1Department of Emergency Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital, Shanghai, 200000 People's Republic of China
| | - Hui Xu
- 1Department of Emergency Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital, Shanghai, 200000 People's Republic of China
| | - Baoan Zhu
- 2Department of Biochemistry, Luohe Medical College, Luohe, 462002 Henan Province People's Republic of China
| | - Zhenling Qiu
- Shandong Yantai Laiyang Center Hospital, 111 Changshan Road, Laiyang, 265200 Shandong Province China
| | - Zaijun Lin
- The Orthopedic Department of Shanghai Hospital of Traditional Chinese Medicine, 274 Zhijiang Middle Road, Jing'an District, Shanghai, 200000 People's Republic of China
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24
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The Extracellular Matrix and Pancreatic Cancer: A Complex Relationship. Cancers (Basel) 2018; 10:cancers10090316. [PMID: 30200666 PMCID: PMC6162452 DOI: 10.3390/cancers10090316] [Citation(s) in RCA: 189] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 08/31/2018] [Accepted: 09/02/2018] [Indexed: 12/18/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has an extraordinarily dense fibrotic stroma that impedes tumor perfusion and delivery of anticancer drugs. Since the extracellular matrix (ECM) comprises the bulk of the stroma, it is primarily responsible for the increased interstitial tissue pressure and stiff mechanical properties of the stroma. Besides its mechanical influence, the ECM provides important biochemical and physical cues that promote survival, proliferation, and metastasis. By serving as a nutritional source, the ECM also enables PDAC cells to survive under the nutrient-poor conditions. While therapeutic strategies using stroma-depleting drugs have yielded disappointing results, an increasing body of research indicates the ECM may offer a variety of potential therapeutic targets. As preclinical studies of ECM-targeted drugs have shown promising effects, a number of clinical trials are currently investigating agents with the potential to advance the future treatment of PDAC. Thus, the present review seeks to give an overview of the complex relationship between the ECM and PDAC.
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25
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Liu Y, Starr MD, Brady JC, Rushing C, Pang H, Adams B, Alvarez D, Theuer CP, Hurwitz HI, Nixon AB. Modulation of Circulating Protein Biomarkers in Cancer Patients Receiving Bevacizumab and the Anti-Endoglin Antibody, TRC105. Mol Cancer Ther 2018; 17:2248-2256. [DOI: 10.1158/1535-7163.mct-17-0916] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 02/23/2018] [Accepted: 07/06/2018] [Indexed: 11/16/2022]
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26
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Hussein K, Suttorp M, Stucki-Koch A, Baumann I, Niemeyer CM, Kreipe H. Molecular profile of inflammatory and megakaryocytic factors in pediatric myelodysplastic syndrome with acute myelofibrosis. Pediatr Blood Cancer 2018; 65:e27048. [PMID: 29667765 DOI: 10.1002/pbc.27048] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 01/16/2018] [Indexed: 11/08/2022]
Abstract
Pediatric fibrotic myelodysplastic syndromes (ped-MDS-MF) and pediatric primary myelofibrosis (ped-PMF) are rare, and the molecular changes which mediate fibrosis have never been investigated. Histology and gene expression profile of 119 fibrosis/angiogenesis/inflammation/megakaryopoiesis-related factors in bone marrow biopsies were performed (two ped-MDS-MF and one ped-PMF). In one progressive ped-MDS, comparison of MF grade 0 (no myelofibrosis) and MF grade 2 (dense network of reticulin fibres) after 4 months showed that expression of fibrosis-related transcripts increased and dysplastic megakaryocytes formed a dense net of CD42b+ proplatelets. These changes were not observed in another ped-MDS-MF, whereas ped-PMF showed a similar proplatelet pattern. These findings indicate that fibrotic changes in ped-MDS may involve proplatelet-related and unrelated pathways.
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Affiliation(s)
- Kais Hussein
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Meinolf Suttorp
- Division of Pediatric Hematology and Oncology, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
| | | | - Irith Baumann
- Institute of Pathology, Health Center Böblingen, Böblingen, Germany
| | - Charlotte M Niemeyer
- Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
| | - Hans Kreipe
- Institute of Pathology, Hannover Medical School, Hannover, Germany
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27
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Profile of fibrosis-related gene transcripts and megakaryocytic changes in the bone marrow of myelodysplastic syndromes with fibrosis. Ann Hematol 2018; 97:2099-2106. [DOI: 10.1007/s00277-018-3411-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 06/21/2018] [Indexed: 11/26/2022]
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28
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Filipe EC, Chitty JL, Cox TR. Charting the unexplored extracellular matrix in cancer. Int J Exp Pathol 2018; 99:58-76. [PMID: 29671911 DOI: 10.1111/iep.12269] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Accepted: 02/26/2018] [Indexed: 12/12/2022] Open
Abstract
The extracellular matrix (ECM) is present in all solid tissues and considered a master regulator of cell behaviour and phenotype. The importance of maintaining the correct biochemical and biophysical properties of the ECM, and the subsequent regulation of cell and tissue homeostasis, is illustrated by the simple fact that the ECM is highly dysregulated in many different types of disease, especially cancer. The loss of tissue ECM homeostasis and integrity is seen as one of the hallmarks of cancer and typically defines transitional events in progression and metastasis. The vast majority of cancer studies place an emphasis on exploring the behaviour and intrinsic signalling pathways of tumour cells. Their goal was to identify ways to target intracellular pathways regulating cancer. Cancer progression and metastasis are powerfully influenced by the ECM and thus present a vast, unexplored repository of anticancer targets that we are only just beginning to tap into. Deconstructing the complexity of the tumour ECM landscape and identifying the interactions between the many cell types, soluble factors and extracellular-matrix proteins have proved challenging. Here, we discuss some of the emerging tools and platforms being used to catalogue and chart the ECM in cancer.
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Affiliation(s)
- Elysse C Filipe
- Cancer Division, Garvan Institute of Medical Research & The Kinghorn Cancer Centre, Sydney, New South Wales, Australia
| | - Jessica L Chitty
- Cancer Division, Garvan Institute of Medical Research & The Kinghorn Cancer Centre, Sydney, New South Wales, Australia
| | - Thomas R Cox
- Cancer Division, Garvan Institute of Medical Research & The Kinghorn Cancer Centre, Sydney, New South Wales, Australia.,Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Sydney, New South Wales, Australia
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29
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Huang YT, Lan Q, Lorusso G, Duffey N, Rüegg C. The matricellular protein CYR61 promotes breast cancer lung metastasis by facilitating tumor cell extravasation and suppressing anoikis. Oncotarget 2018; 8:9200-9215. [PMID: 27911269 PMCID: PMC5354725 DOI: 10.18632/oncotarget.13677] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Accepted: 11/19/2016] [Indexed: 12/22/2022] Open
Abstract
Matricellular proteins play multiple roles in primary tumor growth, local invasion and tumor angiogenesis. However, their contribution to metastasis and the putative mechanisms involved are less well characterized. In ER-negative human breast cancer, elevated expression levels of the matricellular protein Cysteine-rich angiogenic inducer 61 (CYR61) are associated with more aggressive progression. Here, we investigated the role of CYR61 in breast cancer lung metastasis using the triple negative human breast cancer cell lines MDA-MB-231 and SUM159. Silencing of CYR61 significantly decreased lung metastasis from tumors orthotopically implanted in pre-irradiated or naive mammary tissue and upon tail vein injection. Constitutive CYR61 silencing impaired cancer cell extravasation to the lung during the first 24 hours after tail vein injection. In contrast, CYR61 inducible silencing starting 24 hours after cancer cell injection had no impact on lung metastasis formation. In vitro experiments revealed that CYR61 silencing decreased cancer cell transendothelial migration and motility, reduced CYR61 levels present at the cell surface and sensitized cancer cells to anoikis. Furthermore, we demonstrate that CYR61-dependent cell survival under non-adhesive conditions relied, at least partially, on β1 integrin ligation and AMPKα signaling while it was independent of AKT, FAK and ERK1/2 activation. Our data provide the first evidence that CYR61 promotes breast cancer lung metastasis by facilitating tumor cell extravasation and protecting from anoikis during initial seeding to the lung. The uncovered CYR61-β1 integrin-AMPKα axis may serve as a potential therapeutic target to prevent breast cancer metastasis to the lung.
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Affiliation(s)
- Yu-Ting Huang
- Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, Switzerland.,National Center for Competence in Research (NCCR), Molecular Oncology, Swiss Institute for Experimental Cancer Research (ISREC)-Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Qiang Lan
- Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, Switzerland.,National Center for Competence in Research (NCCR), Molecular Oncology, Swiss Institute for Experimental Cancer Research (ISREC)-Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Girieca Lorusso
- Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, Switzerland.,National Center for Competence in Research (NCCR), Molecular Oncology, Swiss Institute for Experimental Cancer Research (ISREC)-Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Nathalie Duffey
- Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, Switzerland
| | - Curzio Rüegg
- Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, Switzerland.,National Center for Competence in Research (NCCR), Molecular Oncology, Swiss Institute for Experimental Cancer Research (ISREC)-Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
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30
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Huang XQ, Zhou ZQ, Zhang XF, Chen CL, Tang Y, Zhu Q, Zhang JH, Xia JC. Overexpression of SMOC2 Attenuates the Tumorigenicity of Hepatocellular Carcinoma Cells and Is Associated With a Positive Postoperative Prognosis in Human Hepatocellular Carcinoma. J Cancer 2017; 8:3812-3827. [PMID: 29151969 PMCID: PMC5688935 DOI: 10.7150/jca.20775] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 08/21/2017] [Indexed: 01/05/2023] Open
Abstract
Secreted modular calcium binding protein-2 (SMOC2), a recently identified matricellular protein that belongs to the SPARC protein family, has been reported to be downregulated in various cancers. The purpose of this study was to investigate the clinical significance and biological function of SMOC2 in human hepatocellular carcinoma. Real-time quantitative PCR and western blotting analyses revealed that SMOC2 mRNA and protein levels were significantly downregulated in human HCC tissues compared to the matched adjacent normal tissues. Clinicopathological analysis indicated that SMOC2 expression was significantly associated with tumor size, number of tumors, tumor-node-metastasis (TNM) stage and distant metastasis. Kaplan-Meier survival analysis showed that high tumor SMOC2 expression was associated with improved overall survival and disease-free survival in patients with HCC. Functional analyses (cell proliferation and colony formation assays, cell migration and invasion assays, cell cycle and apoptosis assays) demonstrated that stable overexpression of SMOC2 using a lentiviral vector significantly inhibited cell proliferation, colony formation, migration and invasion, and induced G0/G1 phase arrest in HCC cells in vitro. In addition, experiments with a mouse model revealed the suppressed effect of SMOC2 on HCC tumorigenicity and metastases in vivo. These results suggest that SMOC2 functions as a tumor suppressor during the development of HCC and may represent an effective prognostic factor and novel therapeutic target for HCC.
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Affiliation(s)
- Xu-Qiong Huang
- Huadu District People's Hospital of Guangzhou, Southern Medical University, Guangzhou, Guangdong province, 510800, China.,Department of Epidemiology and Health Statistics, Guangdong Pharmaceutical University, Guangzhou, Guangdong province, 510010, China
| | - Zi-Qi Zhou
- State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong province, 510060, China
| | - Xiao-Fei Zhang
- State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong province, 510060, China
| | - Chang-Long Chen
- State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong province, 510060, China
| | - Yan Tang
- State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong province, 510060, China
| | - Qian Zhu
- State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong province, 510060, China
| | - Jian-Hua Zhang
- Department of Epidemiology and Health Statistics, Guangdong Pharmaceutical University, Guangzhou, Guangdong province, 510010, China.,Department of Health Service Management, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong province, 510006, China
| | - Jian-Chuan Xia
- State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong province, 510060, China
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31
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Hsieh HY, Jou YC, Tung CL, Tsai YS, Wang YH, Chi CL, Lin RI, Hung SK, Chuang YM, Wu SF, Li C, Shen CH, Chan MWY, Hsu CD. Epigenetic silencing of the dual-role signal mediator, ANGPTL4 in tumor tissues and its overexpression in the urothelial carcinoma microenvironment. Oncogene 2017; 37:673-686. [PMID: 29035390 DOI: 10.1038/onc.2017.375] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Revised: 09/03/2017] [Accepted: 09/07/2017] [Indexed: 12/22/2022]
Abstract
Urothelial carcinoma (UC) carcinogenesis has been hypothesized to occur through epigenetic repression of tumor-suppressor genes (TSGs). By quantitative real-time polymerase chain reaction array, we found that one potential TSG, angiopoietin-like 4 (ANGPTL4), was expressed at very low levels in all bladder cancer cell lines we examined. Previous studies had demonstrated that ANGPTL4 is highly expressed in some cancers, but downregulated, by DNA methylation, in others. Consequently, owing to these seemingly conflicting functions in distinct cancers, the precise role of ANGPTL4 in the etiology of UC remains unclear. In this study, using methylation-specific PCR and bisulfite pyrosequencing, we show that ANGPTL4 is transcriptionally repressed by DNA methylation in UC cell lines and primary tumor samples, as compared with adjacent noncancerous bladder epithelium. Functional studies further demonstrated that ectopic expression of ANGPTL4 potently suppressed UC cell proliferation, monolayer colony formation in vitro, and invasion, migration, and xenograft formation in vivo. Surprisingly, circulating ANGPTL4 was significantly higher in plasma samples from UC patients than normal control, suggesting it might be secreted from other cell types. Interestingly, our data also indicated that exogenous cANGPTL4 could promote cell proliferation and cell migration via activation of signaling through the Erk/focal adhesion kinase axis. We further confirmed that mouse xenograft tumor growth could be promoted by administration of exogenous cANGPTL4. Finally, immunohistochemistry demonstrated that ANGPTL4 was downregulated in tumor cells but overexpressed in tumor adjacent stromal tissues of muscle-invasive UC tissue samples. In conclusion, our data support dual roles for ANGPTL4 in UC progression, either as a tumor suppressor or oncogene, in response to microenvironmental context.
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Affiliation(s)
- H-Y Hsieh
- Department of Medical Research, Ditmanson Medical Fountain Chiayi Christian Hospital, Chiayi, Taiwan.,Department of Urology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan.,Department of Life Science, National Chung Cheng University, Chiayi, Taiwan.,Department of Biology, National Museum of Natural Science, Taichung, Taiwan
| | - Y-C Jou
- Department of Urology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan
| | - C-L Tung
- Department of Pathology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan
| | - Y-S Tsai
- Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Y-H Wang
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Division of General Surgery, Department of Urology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - C-L Chi
- Department of Pathology, Buddhist Dalin Tzu Chi General Hospital, Chiayi, Taiwan
| | - R-I Lin
- Department of Radiation Oncology, Buddhist Dalin Tzu Chi General Hospital, Chiayi, Taiwan
| | - S-K Hung
- Department of Radiation Oncology, Buddhist Dalin Tzu Chi General Hospital, Chiayi, Taiwan.,School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Y-M Chuang
- Department of Life Science, National Chung Cheng University, Chiayi, Taiwan.,Institute of Molecular Biology, National Chung Cheng University, Chiayi, Taiwan
| | - S-F Wu
- Department of Life Science, National Chung Cheng University, Chiayi, Taiwan.,Institute of Molecular Biology, National Chung Cheng University, Chiayi, Taiwan
| | - C Li
- Department of Life Science, National Chung Cheng University, Chiayi, Taiwan.,Institute of Molecular Biology, National Chung Cheng University, Chiayi, Taiwan
| | - C-H Shen
- Department of Urology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan
| | - M W Y Chan
- Department of Life Science, National Chung Cheng University, Chiayi, Taiwan.,Institute of Molecular Biology, National Chung Cheng University, Chiayi, Taiwan
| | - C-D Hsu
- Department of Medical Research, Ditmanson Medical Fountain Chiayi Christian Hospital, Chiayi, Taiwan.,Department of Urology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan.,Department of Life Science, National Chung Cheng University, Chiayi, Taiwan
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32
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Chen PC, Tai HC, Lin TH, Wang SW, Lin CY, Chao CC, Yu HJ, Tsai YC, Lai YW, Lin CW, Tang CH. CCN3 promotes epithelial-mesenchymal transition in prostate cancer via FAK/Akt/HIF-1α-induced twist expression. Oncotarget 2017; 8:74506-74518. [PMID: 29088803 PMCID: PMC5650358 DOI: 10.18632/oncotarget.20171] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Accepted: 06/29/2017] [Indexed: 02/04/2023] Open
Abstract
Epithelial-mesenchymal transition (EMT) has received considerable attention as a conceptual paradigm for explaining metastatic behavior during cancer progression. NOV/CCN3 is a matrix-associated protein involved in many cellular functions. Previous studies have shown that CCN3 expression is upregulated in prostate cancer (PCa) cells and in PCa patients. In this study, we have provided evidence of tumor promoting effects of CCN3, which includes induction of epithelial-to-mesenchymal transition (EMT) and tumor metastasis. We used an orthotopic in vivo model to demonstrate the prometastatic effects of CCN3. Overexpression or knockdown of CCN3 changed the EMT phenotype in PCa cells. Moreover, treatment with recombinant CCN3 promoted EMT in PCa cells. We also found that CCN3 may promote EMT by activating the FAK/Akt/HIF-1α pathway and this activation is responsible for Twist expression. IHC staining confirmed a positive correlation between the expression of CCN3, Twist, and tumor stage in PCa tissue. Our findings provide insight into the involvement of CCN3 in the EMT regulation of prostate cancer. CCN3 is a promising molecular target that may contribute to a novel therapeutic strategy against metastatic PCa.
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Affiliation(s)
- Po-Chun Chen
- Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan.,Department of Medical Research, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung, Taiwan.,Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
| | - Huai-Ching Tai
- Department of Urology, National Taiwan University Hospital, Taipei, Taiwan.,Department of Urology, Fu-Jen Catholic University Hospital, New Taipei City, Taiwan.,School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan
| | - Tien-Huang Lin
- Department of Urology, Buddhist Tzu Chi General Hospital Taichung Branch, Taichung, Taiwan.,School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan
| | - Shih-Wei Wang
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
| | - Chih-Yang Lin
- Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan
| | - Chia-Chia Chao
- Department of Respiratory Therapy, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Hong-Jeng Yu
- Department of Urology, National Taiwan University Hospital, Taipei, Taiwan
| | - Yu-Chieh Tsai
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Yu-Wei Lai
- Division of Urology, Taipei City Hospital Renai Branch, Taipei, Taiwan.,Department of Urology, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Chiao-Wen Lin
- Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan.,Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chih-Hsin Tang
- Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan.,Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan.,Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
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33
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Izraely S, Ben-Menachem S, Sagi-Assif O, Meshel T, Marzese DM, Ohe S, Zubrilov I, Pasmanik-Chor M, Hoon DSB, Witz IP. ANGPTL4 promotes the progression of cutaneous melanoma to brain metastasis. Oncotarget 2017; 8:75778-75796. [PMID: 29100268 PMCID: PMC5652662 DOI: 10.18632/oncotarget.19018] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 06/10/2017] [Indexed: 01/16/2023] Open
Abstract
In an ongoing effort to identify molecular determinants regulating melanoma brain metastasis, we previously identified Angiopoietin-like 4 (ANGPTL4) as a component of the molecular signature of such metastases. The aim of this study was to determine the functional significance of ANGPTL4 in the shaping of melanoma malignancy phenotype, especially in the establishment of brain metastasis. We confirmed that ANGPTL4 expression is significantly higher in cells metastasizing to the brain than in cells from the cutaneous (local) tumor from the same melanoma in a nude mouse xenograft model, and also in paired clinical specimens of melanoma metastases than in primary melanomas from the same patients. In vitro experiments indicated that brain-derived soluble factors and transforming growth factor β1 (TGFβ1) up-regulated ANGPTL4 expression by melanoma cells. Forced over-expression of ANGPTL4 in cutaneous melanoma cells promoted their ability to adhere and transmigrate brain endothelial cells. Over-expressing ANGPTL4 in cells derived from brain metastases resulted in the opposite effects. In vivo data indicated that forced overexpression of ANGPTL4 promoted the tumorigenicity of cutaneous melanoma cells but did not increase their ability to form brain metastasis. This finding can be explained by inhibitory activities of brain-derived soluble factors. Taken together these findings indicate that ANGPTL4 promotes the malignancy phenotype of primary melanomas of risk to metastasize to the brain.
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Affiliation(s)
- Sivan Izraely
- Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Shlomit Ben-Menachem
- Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Orit Sagi-Assif
- Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Tsipi Meshel
- Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Diego M Marzese
- Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA
| | - Shuichi Ohe
- Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA
| | - Inna Zubrilov
- Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Metsada Pasmanik-Chor
- Bioinformatics Unit, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Dave S B Hoon
- Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA
| | - Isaac P Witz
- Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
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34
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ANGPTL4 T266M variant is associated with reduced cancer invasiveness. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2017. [PMID: 28641978 DOI: 10.1016/j.bbamcr.2017.06.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Angiopoietin-like 4 (ANGPTL4) is a secretory protein that can be cleaved to form an N-terminal and a C-terminal protein. Studies performed thus far have linked ANGPTL4 to several cancer-related and metabolic processes. Notably, several point mutations in the C-terminal ANGPTL4 (cANGPTL4) have been reported, although no studies have been performed that ascribed these mutations to cancer-related and metabolic processes. In this study, we compared the characteristics of tumors with and without wild-type (wt) cANGPTL4 and tumors with cANGPTL4 bearing the T266M mutation (T266M cANGPTL4). We found that T266M cANGPTL4 bound to integrin α5β1 with a reduced affinity compared to wt, leading to weaker activation of downstream signaling molecules. The mutant tumors exhibited impaired proliferation, anoikis resistance, and migratory capability and had reduced adenylate energy charge. Further investigations also revealed that cANGPTL4 regulated the expression of Glut2. These findings may explain the differences in the tumor characteristics and energy metabolism observed with the cANGPTL4 T266M mutation compared to tumors without the mutation.
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35
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Tenascin-C and fibronectin expression divide early stage tongue cancer into low- and high-risk groups. Br J Cancer 2017; 116:640-648. [PMID: 28095396 PMCID: PMC5344290 DOI: 10.1038/bjc.2016.455] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 11/18/2016] [Accepted: 12/20/2016] [Indexed: 12/23/2022] Open
Abstract
Background: Oral tongue squamous cell carcinoma (OTSCC) metastasises early, especially to regional lymph nodes. There is an ongoing debate on which early stage (T1-T2N0) patients should be treated with elective neck dissection. We need prognosticators for early stage tongue cancer. Methods: Mice immunisation with human mesenchymal stromal cells resulted in production of antibodies against tenascin-C (TNC) and fibronectin (FN), which were used to stain 178 (98 early stage), oral tongue squamous cell carcinoma samples. Tenascin-C and FN expression in the stroma (negative, moderate or abundant) and tumour cells (negative or positive) were assessed. Similar staining was obtained using corresponding commercial antibodies. Results: Expression of TNC and FN in the stroma, but not in the tumour cells, proved to be excellent prognosticators both in all stages and in early stage cases. Among early stages, when stromal TNC was negative, the 5-year survival rate was 88%. Correspondingly, when FN was negative, no cancer deaths were observed. Five-year survival rates for abundant expression of TNC and FN were 43% and 25%, respectively. Conclusions: Stromal TNC and, especially, FN expressions differentiate patients into low- and high-risk groups. Surgery alone of early stage primary tumours might be adequate when stromal FN is negative. Aggressive treatments should be considered when both TNC and FN are abundant.
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36
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Polat B, Kaiser P, Wohlleben G, Gehrke T, Scherzad A, Scheich M, Malzahn U, Fischer T, Vordermark D, Flentje M. Perioperative changes in osteopontin and TGFβ1 plasma levels and their prognostic impact for radiotherapy in head and neck cancer. BMC Cancer 2017; 17:6. [PMID: 28049456 PMCID: PMC5209814 DOI: 10.1186/s12885-016-3024-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 12/20/2016] [Indexed: 11/10/2022] Open
Abstract
Background In head and neck cancer little is known about the kinetics of osteopontin (OPN) expression after tumor resection. In this study we evaluated the time course of OPN plasma levels before and after surgery. Methods Between 2011 and 2013 41 consecutive head and neck cancer patients were enrolled in a prospective study (group A). At different time points plasma samples were collected: T0) before, T1) 1 day, T2) 1 week and T3) 4 weeks after surgery. Osteopontin and TGFβ1 plasma concentrations were measured with a commercial ELISA system. Data were compared to 131 head and neck cancer patients treated with primary (n = 42) or postoperative radiotherapy (n = 89; group B1 and B2). Results A significant OPN increase was seen as early as 1 day after surgery (T0 to T1, p < 0.01). OPN levels decreased to base line 3-4 weeks after surgery. OPN values were correlated with postoperative TGFβ1 expression suggesting a relation to wound healing. Survival analysis showed a significant benefit for patients with lower OPN levels both in the primary and postoperative radiotherapy group (B1: 33 vs 11.5 months, p = 0.017, B2: median not reached vs 33.4, p = 0.031). TGFβ1 was also of prognostic significance in group B1 (33.0 vs 10.7 months, p = 0.003). Conclusions Patients with head and neck cancer showed an increase in osteopontin plasma levels directly after surgery. Four weeks later OPN concentration decreased to pre-surgery levels. This long lasting increase was presumably associated to wound healing. Both pretherapeutic osteopontin and TGFβ1 had prognostic impact.
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Affiliation(s)
- Bülent Polat
- Department of Radiation Oncology, University of Würzburg, Josef-Schneider-Straße 11, 97080, Würzburg, Germany.
| | - Philipp Kaiser
- Department of Radiation Oncology, University of Würzburg, Josef-Schneider-Straße 11, 97080, Würzburg, Germany
| | - Gisela Wohlleben
- Department of Radiation Oncology, University of Würzburg, Josef-Schneider-Straße 11, 97080, Würzburg, Germany
| | - Thomas Gehrke
- Department of Oto-Rhino-Laryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, University of Würzburg, Würzburg, Germany
| | - Agmal Scherzad
- Department of Oto-Rhino-Laryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, University of Würzburg, Würzburg, Germany
| | - Matthias Scheich
- Department of Oto-Rhino-Laryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, University of Würzburg, Würzburg, Germany
| | - Uwe Malzahn
- Department of Epidemiology and Biostatistics, University of Würzburg, Würzburg, Germany
| | - Thomas Fischer
- Department of Radiation Oncology, University of Würzburg, Josef-Schneider-Straße 11, 97080, Würzburg, Germany
| | - Dirk Vordermark
- Department of Radiation Oncology, University of Halle-Wittenberg, Halle, Germany
| | - Michael Flentje
- Department of Radiation Oncology, University of Würzburg, Josef-Schneider-Straße 11, 97080, Würzburg, Germany
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Yu T, Di G. Role of tumor microenvironment in triple-negative breast cancer and its prognostic significance. Chin J Cancer Res 2017; 29:237-252. [PMID: 28729775 PMCID: PMC5497211 DOI: 10.21147/j.issn.1000-9604.2017.03.10] [Citation(s) in RCA: 119] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Breast cancer has been shown to live in the tumor microenvironment, which consists of not only breast cancer cells themselves but also a significant amount of pathophysiologically altered surrounding stroma and cells. Diverse components of the breast cancer microenvironment, such as suppressive immune cells, re-programmed fibroblast cells, altered extracellular matrix (ECM) and certain soluble factors, synergistically impede an effective anti-tumor response and promote breast cancer progression and metastasis. Among these components, stromal cells in the breast cancer microenvironment are characterized by molecular alterations and aberrant signaling pathways, whereas the ECM features biochemical and biomechanical changes. However, triple-negative breast cancer (TNBC), the most aggressive subtype of this disease that lacks effective therapies available for other subtypes, is considered to feature a unique microenvironment distinct from that of other subtypes, especially compared to Luminal A subtype. Because these changes are now considered to significantly impact breast cancer development and progression, these unique alterations may serve as promising prognostic factors of clinical outcome or potential therapeutic targets for the treatment of TNBC. In this review, we focus on the composition of the TNBC microenvironment, concomitant distinct biological alteration, specific interplay between various cell types and TNBC cells, and the prognostic implications of these findings.
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Affiliation(s)
- Tianjian Yu
- Department of Breast Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Genhong Di
- Department of Breast Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
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Huang YT, Lan Q, Ponsonnet L, Blanquet M, Christofori G, Zaric J, Rüegg C. The matricellular protein CYR61 interferes with normal pancreatic islets architecture and promotes pancreatic neuroendocrine tumor progression. Oncotarget 2016; 7:1663-74. [PMID: 26625209 PMCID: PMC4811488 DOI: 10.18632/oncotarget.6411] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Accepted: 11/15/2015] [Indexed: 12/22/2022] Open
Abstract
The significance of matricellular proteins during development and cancer progression is widely recognized. However, how these proteins actively contribute to physiological development and pathological cancer progression is only partially elucidated. In this study, we investigated the role of the matricellular protein Cysteine-rich 61 (CYR61) in pancreatic islet development and carcinogenesis. Transgenic expression of CYR61 in β cells (Rip1CYR mice) caused irregular islets morphology and distorted sorting of α cells, but did not alter islets size, number or vascularization. To investigate the function of CYR61 during carcinogenesis, we crossed Rip1CYR mice with Rip1Tag2 mice, a well-established model of β cell carcinogenesis. Beta tumors in Rip1Tag2CYR mice were larger, more invasive and more vascularized compared to tumors in Rip1Tag2 mice. The effect of CYR61 on angiogenesis was fully abrogated by treating mice with the anti-VEGFR2 mAb DC101. Results from in vitro assays demonstrated that CYR61 modulated integrin α6β1-dependent invasion and adhesion without altering its expression. Taken together, these results show that CYR61 expression in pancreatic β cells interferes with normal islet architecture, promotes islet tumor growth, invasion and VEGF/VERGFR-2-dependent tumor angiogenesis. Taken together, these observations demonstrate that CYR61 acts as a tumor-promoting gene in pancreatic neuroendocrine tumors.
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Affiliation(s)
- Yu-Ting Huang
- Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, Switzerland.,National Center for Competence in Research (NCCR), Molecular Oncology, Swiss Institute for Experimental Cancer Research (ISREC)-Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Qiang Lan
- Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, Switzerland.,National Center for Competence in Research (NCCR), Molecular Oncology, Swiss Institute for Experimental Cancer Research (ISREC)-Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Lionel Ponsonnet
- Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, Switzerland.,National Center for Competence in Research (NCCR), Molecular Oncology, Swiss Institute for Experimental Cancer Research (ISREC)-Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Marisa Blanquet
- Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, Switzerland
| | - Gerhard Christofori
- National Center for Competence in Research (NCCR), Molecular Oncology, Swiss Institute for Experimental Cancer Research (ISREC)-Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.,Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Jelena Zaric
- Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, Switzerland.,National Center for Competence in Research (NCCR), Molecular Oncology, Swiss Institute for Experimental Cancer Research (ISREC)-Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Curzio Rüegg
- Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, Switzerland.,National Center for Competence in Research (NCCR), Molecular Oncology, Swiss Institute for Experimental Cancer Research (ISREC)-Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
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Dotterweich J, Schlegelmilch K, Keller A, Geyer B, Schneider D, Zeck S, Tower RJJ, Ebert R, Jakob F, Schütze N. Contact of myeloma cells induces a characteristic transcriptome signature in skeletal precursor cells -Implications for myeloma bone disease. Bone 2016; 93:155-166. [PMID: 27519972 DOI: 10.1016/j.bone.2016.08.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Revised: 06/24/2016] [Accepted: 08/08/2016] [Indexed: 10/21/2022]
Abstract
Physical interaction of skeletal precursors with multiple myeloma cells has been shown to suppress their osteogenic potential while favoring their tumor-promoting features. Although several transcriptome analyses of myeloma patient-derived mesenchymal stem cells have displayed differences compared to their healthy counterparts, these analyses insufficiently reflect the signatures mediated by tumor cell contact, vary due to different methodologies, and lack results in lineage-committed precursors. To determine tumor cell contact-mediated changes on skeletal precursors, we performed transcriptome analyses of mesenchymal stem cells and osteogenic precursor cells cultured in contact with the myeloma cell line INA-6. Comparative analyses confirmed dysregulation of genes which code for known disease-relevant factors and additionally revealed upregulation of genes that are associated with plasma cell homing, adhesion, osteoclastogenesis, and angiogenesis. Osteoclast-derived coupling factors, a dysregulated adipogenic potential, and an imbalance in favor of anti-anabolic factors may play a role in the hampered osteoblast differentiation potential of mesenchymal stem cells. Angiopoietin-Like 4 (ANGPTL4) was selected from a list of differentially expressed genes as a myeloma cell contact-dependent target in skeletal precursor cells which warranted further functional analyses. Adhesion assays with full-length ANGPTL4-coated plates revealed a potential role of this protein in INA-6 cell attachment. This study expands knowledge of the myeloma cell contact-induced signature in the stromal compartment of myelomatous bones and thus offers potential targets that may allow detection and treatment of myeloma bone disease at an early stage.
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Affiliation(s)
- Julia Dotterweich
- Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Würzburg, Germany
| | - Katrin Schlegelmilch
- Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Würzburg, Germany
| | - Alexander Keller
- DNA-Analytics Core Facility, Biocenter and Department of Animal Ecology and Tropical Biology, University of Würzburg, Würzburg, Germany
| | - Beate Geyer
- Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Würzburg, Germany
| | - Doris Schneider
- Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Würzburg, Germany
| | - Sabine Zeck
- Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Würzburg, Germany
| | - Robert J J Tower
- Section Biomedical Imaging, MOIN CC, Department of Radiology and Neuroradiology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Regina Ebert
- Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Würzburg, Germany
| | - Franz Jakob
- Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Würzburg, Germany.
| | - Norbert Schütze
- Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Würzburg, Germany
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Thakur R, Mishra DP. Matrix reloaded: CCN, tenascin and SIBLING group of matricellular proteins in orchestrating cancer hallmark capabilities. Pharmacol Ther 2016; 168:61-74. [DOI: 10.1016/j.pharmthera.2016.09.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Danzaki K, Kanayama M, Alcazar O, Shinohara ML. Osteopontin has a protective role in prostate tumor development in mice. Eur J Immunol 2016; 46:2669-2678. [PMID: 27601131 DOI: 10.1002/eji.201646391] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Revised: 08/12/2016] [Accepted: 09/02/2016] [Indexed: 12/25/2022]
Abstract
Osteopontin (OPN) is a protein, generally considered to play a pro-tumorigenic role, whereas several reports have demonstrated the anti-tumorigenic function of OPN during tumor development. These opposing anti- and pro-tumorigenic functions are not fully understood. Here, we report that host-derived OPN plays an anti-tumorigenic role in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model and a TRAMP tumor transplant model. Tumor suppression mediated by OPN in Rag2-/- mice suggests that OPN is dispensable in the adaptive immune response. We found that host-derived OPN enhanced infiltration of natural killer (NK) cells into TRAMP tumors. The requirement of OPN in NK cell migration towards TRAMP cells was confirmed by an ex vivo cell migration assay. In contrast to TRAMP cells, in vivo B16 tumor development was not inhibited by OPN, and B16 tumors did not show OPN-mediated cell recruitment. It is possible that low levels of chemokine expression by B16 cells do not allow OPN to enhance immune cell recruitment. In addition to demonstrating the anti-tumorigenic role of OPN in TRAMP tumor development, this study also suggests that the contribution of OPN to tumor development depends on the type of tumor as well as the source and isoform of OPN.
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Affiliation(s)
- Keiko Danzaki
- Department of Immunology, Duke University Medical School, Durham, NC, 27710, USA
| | - Masashi Kanayama
- Department of Immunology, Duke University Medical School, Durham, NC, 27710, USA
| | - Oscar Alcazar
- Department of Immunology, Duke University Medical School, Durham, NC, 27710, USA
| | - Mari L Shinohara
- Department of Immunology, Duke University Medical School, Durham, NC, 27710, USA. .,Department of Molecular Genetics and Microbiology, Duke University Medical School, Durham, NC, 27710, USA.
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CCN family of proteins: critical modulators of the tumor cell microenvironment. J Cell Commun Signal 2016; 10:229-240. [PMID: 27517291 DOI: 10.1007/s12079-016-0346-6] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2016] [Accepted: 08/02/2016] [Indexed: 02/07/2023] Open
Abstract
The CCN family of proteins consisting of CCN1 (Cyr61), CCN2 (CTGF), CCN3 (NOV), CCN4 (WISP-1), CCN5 (WISP-2) and CCN6 (WISP-3) are considered matricellular proteins operating essentially in the extracellular microenvironment between cells. Evidence has also been gradually building since their first discovery of additional intracellular roles although the major activity is triggered at the cell membrane. The proteins consist of 4 motifs, a signal peptide (for secretion} followed consecutively by the IGFBP, VWC, TSP1 and CT (C-terminal cysteine knot domain) motifs, which signify their potential binding partners and functional connections to a variety of key regulators of physiological processes. With respect to cancer it is now clear that, whereas certain members can facilitate tumor behavior and progression, others can competitively counter the process. It is therefore clear that the net outcome of biological interactions in the matrix and what gets signaled or inhibited can be a function of the interplay of these CCN 1-6 proteins. Because the CCN proteins further interact with other key proteins, like growth factors in the matrix, the balance is not only important but can vary dynamically with the physiological states of tumor cells and the surrounding normal cells. The tumor niche with its many cell players has surfaced as a critical determinant of tumor behavior, invasiveness, and metastasis. It is in this context that CCN proteins should be investigated with the potential of being recognized and validated for future therapeutic approaches.
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43
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Cancer Stem Cell Quiescence and Plasticity as Major Challenges in Cancer Therapy. Stem Cells Int 2016; 2016:1740936. [PMID: 27418931 PMCID: PMC4932171 DOI: 10.1155/2016/1740936] [Citation(s) in RCA: 257] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Accepted: 05/15/2016] [Indexed: 02/06/2023] Open
Abstract
Cells with stem-like properties, tumorigenic potential, and treatment-resistant phenotypes have been identified in many human malignancies. Based on the properties they share with nonneoplastic stem cells or their ability to initiate and propagate tumors in vivo, such cells were designated as cancer stem (stem-like) or tumor initiating/propagating cells. Owing to their implication in treatment resistance, cancer stem cells (CSCs) have been the subject of intense investigation in past years. Comprehension of CSCs' intrinsic properties and mechanisms they develop to survive and even enhance their aggressive phenotype within the hostile conditions of the tumor microenvironment has reoriented therapeutic strategies to fight cancer. This report provides selected examples of malignancies in which the presence of CSCs has been evidenced and briefly discusses methods to identify, isolate, and functionally characterize the CSC subpopulation of cancer cells. Relevant biological targets in CSCs, their link to treatment resistance, proposed targeting strategies, and limitations of these approaches are presented. Two major aspects of CSC physiopathology, namely, relative in vivo quiescence and plasticity in response to microenvironmental cues or treatment, are highlighted. Implications of these findings in the context of the development of new therapies are discussed.
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44
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Johnson RH, Hu P, Fan C, Anders CK. Gene expression in "young adult type" breast cancer: a retrospective analysis. Oncotarget 2016; 6:13688-702. [PMID: 25999348 PMCID: PMC4537042 DOI: 10.18632/oncotarget.4051] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2015] [Accepted: 04/03/2015] [Indexed: 11/25/2022] Open
Abstract
Background: Young women with breast cancer experience inferior outcome and commonly manifest aggressive biological subtypes. Data is controversial regarding biological differences between breast tumors in young (diagnosed at <40 years of age) versus older women. We hypothesize there may be age-related expression differences in key genes for proliferation, invasion and metastasis within and across breast cancer subtypes, and that these differences correlate with outcome. Methods: Using clinically-annotated gene expression data from 778 breast tumors from three public databases, we compared clinico-pathologic characteristics, mRNA expression of 17 selected genes, and outcome, as a function of age (< 40 years vs. ≥ 40 years). Results: 14 of 17 genes were differentially expressed in tumors of young vs. older women, 4 of which persisted after correction for subtype and grade (p ≤0.05). BUB1, KRT5, and MYCN were overexpressed and CXCL2 underexpressed in young women. In multivariate analysis, overexpression of cytokeratin genes predicted inferior DFS only for young women. Overexpression of ANGPTL4 strongly predicted inferior DFS in basal but not HER2-enriched tumors in young women. Overexpression of cytokeratin genes and MYBL2 and low SNAI1 expression correlated with inferior DFS in HER2-enriched tumors in younger women. Kaplan-Meier analysis within the basal and HER2-enriched subgroups showed that overexpression of cytokeratin genes was associated with inferior DFS for young, but not older women. Conclusions: This preliminary study reveals age- and subtype-related differences in expression of key breast cancer genes for proliferation, invasion and metastasis, which correlate with prognostic differences in young women and suggest targeted therapies.
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Affiliation(s)
- Rebecca H Johnson
- Seattle Children's Hospital/University of Washington, Seattle, WA, USA
| | - Pingzhao Hu
- Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada
| | - Cheng Fan
- University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA
| | - Carey K Anders
- University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.,Department of Medicine, Division of Hematology-Oncology, University of North Carolina, Chapel Hill, NC, USA
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Sawyer AJ, Kyriakides TR. Matricellular proteins in drug delivery: Therapeutic targets, active agents, and therapeutic localization. Adv Drug Deliv Rev 2016; 97:56-68. [PMID: 26763408 DOI: 10.1016/j.addr.2015.12.016] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Revised: 12/17/2015] [Accepted: 12/17/2015] [Indexed: 02/06/2023]
Abstract
Extracellular matrix is composed of a complex array of molecules that together provide structural and functional support to cells. These properties are mainly mediated by the activity of collagenous and elastic fibers, proteoglycans, and proteins such as fibronectin and laminin. ECM composition is tissue-specific and could include matricellular proteins whose primary role is to modulate cell-matrix interactions. In adults, matricellular proteins are primarily expressed during injury, inflammation and disease. Particularly, they are closely associated with the progression and prognosis of cardiovascular and fibrotic diseases, and cancer. This review aims to provide an overview of the potential use of matricellular proteins in drug delivery including the generation of therapeutic agents based on the properties and structures of these proteins as well as their utility as biomarkers for specific diseases.
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The extracellular matrix in breast cancer. Adv Drug Deliv Rev 2016; 97:41-55. [PMID: 26743193 DOI: 10.1016/j.addr.2015.12.017] [Citation(s) in RCA: 292] [Impact Index Per Article: 32.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Revised: 12/18/2015] [Accepted: 12/19/2015] [Indexed: 12/31/2022]
Abstract
The extracellular matrix (ECM) is increasingly recognized as an important regulator in breast cancer. ECM in breast cancer development features numerous changes in composition and organization when compared to the mammary gland under homeostasis. Matrix proteins that are induced in breast cancer include fibrillar collagens, fibronectin, specific laminins and proteoglycans as well as matricellular proteins. Growing evidence suggests that many of these induced ECM proteins play a major functional role in breast cancer progression and metastasis. A number of the induced ECM proteins have moreover been shown to be essential components of metastatic niches, promoting stem/progenitor signaling pathways and metastatic growth. ECM remodeling enzymes are also markedly increased, leading to major changes in the matrix structure and biomechanical properties. Importantly, several ECM components and ECM remodeling enzymes are specifically induced in breast cancer or during tissue regeneration while healthy tissues under homeostasis express exceedingly low levels. This may indicate that ECM and ECM-associated functions may represent promising drug targets against breast cancer, providing important specificity that could be utilized when developing therapies.
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Trotter TN, Yang Y. Matricellular proteins as regulators of cancer metastasis to bone. Matrix Biol 2016; 52-54:301-314. [PMID: 26807761 DOI: 10.1016/j.matbio.2016.01.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Revised: 01/19/2016] [Accepted: 01/19/2016] [Indexed: 01/08/2023]
Abstract
Metastasis is the major cause of death in cancer patients, and a frequent site of metastasis for many cancers is the bone marrow. Therefore, understanding the mechanisms underlying the metastatic process is necessary for future prevention and treatment. The tumor microenvironment is now known to play a role in the metastatic cascade, both at the primary tumor and in metastatic sites, and includes both cellular and non-cellular components. The extracellular matrix (ECM) provides structural support and signaling cues to cells. One particular group of molecules associated with the ECM, known as matricellular proteins, modulate multiple aspects of tumor biology, including growth, migration, invasion, angiogenesis and metastasis. These proteins are also important for normal function in the bone by regulating bone formation and bone resorption. Recent studies have described a link between some of these proteins and metastasis of various tumors to the bone. The aim of this review is to summarize what is currently known about matricellular protein influence on bone metastasis. Particular attention to the contribution of both tumor cells and non-malignant cells in the bone has been given.
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Affiliation(s)
- Timothy N Trotter
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Yang Yang
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States; Comprehensive Cancer Center and the Center for Metabolic Bone Disease, University of Alabama at Birmingham, Birmingham, AL, United States.
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48
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Extracellular matrix-mediated cellular communication in the heart. J Mol Cell Cardiol 2016; 91:228-37. [PMID: 26778458 DOI: 10.1016/j.yjmcc.2016.01.011] [Citation(s) in RCA: 99] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Revised: 01/10/2016] [Accepted: 01/11/2016] [Indexed: 01/13/2023]
Abstract
The extracellular matrix (ECM) is a complex and dynamic scaffold that maintains tissue structure and dynamics. However, the view of the ECM as an inert architectural support has been increasingly challenged. The ECM is a vibrant meshwork, a crucial organizer of cellular microenvironments. It plays a direct role in cellular interactions regulating cell growth, survival, spreading, proliferation, differentiation and migration through the intricate relationship among cellular and acellular tissue components. This complex interrelationship preserves cardiac function during homeostasis; however it is also responsible for pathologic remodeling following myocardial injury. Therefore, enhancing our understanding of this cross-talk may provide mechanistic insights into the pathogenesis of heart failure and suggest new approaches to novel, targeted pharmacologic therapies. This review explores the implications of ECM-cell interactions in myocardial cell behavior and cardiac function at baseline and following myocardial injury.
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Osteopontin-integrin interaction as a novel molecular target for antibody-mediated immunotherapy in adult T-cell leukemia. Retrovirology 2015; 12:99. [PMID: 26597716 PMCID: PMC4657376 DOI: 10.1186/s12977-015-0225-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Accepted: 11/12/2015] [Indexed: 12/18/2022] Open
Abstract
Background Adult T-cell leukemia (ATL) is a CD4+ T-cell neoplasm with a poor prognosis. A previous study has shown that there is a strong correlation between the secreted matricellular protein osteopontin (OPN) level and disease severity in ATL patients. Here, we investigated the role of OPN in ATL pathogenesis and the possible application of anti-OPN monoclonal antibody (mAb) for ATL immunotherapy in NOD/Shi-scid,IL-2Rgnull (NOG) mice. Results Subcutaneous inoculation of ATL cell lines into NOG mice increased the plasma level of OPN, which significantly correlated with metastasis of the inoculated cells and survival time. Administration of an SVVYGLR motif-recognizing anti-OPN mAb resulted in inhibition not only of tumor growth but also of tumor invasion and metastasis. The number of fibroblast activating protein-positive fibroblasts was also reduced by this mAb. We then co-inoculated mouse embryonic fibroblasts (MEFs) isolated from wild-type (WT) or OPN knockout mice together with ATL-derived TL-OmI cells into the NOG mice. The mice co-inoculated with WT MEFs displayed a significant decrease in survival relative to those injected with TL-OmI cells alone and the absence of OPN in MEFs markedly improved the survival rate of TL-OmI-inoculated mice. In addition, tumor volume and metastasis were also reduced in the absence of OPN. Conclusion We showed that the xenograft NOG mice model can be a useful system for assessment of the physiological role of OPN in ATL pathogenesis. Using this xenograft model, we found that fibroblast-derived OPN was involved in tumor growth and metastasis, and that this tumor growth and metastasis was significantly suppressed by administration of the anti-OPN mAbs. Our findings will lead to a novel mAb-mediated immunotherapeutic strategy targeting against the interaction of OPN with integrins on the tumor of ATL patients. Electronic supplementary material The online version of this article (doi:10.1186/s12977-015-0225-x) contains supplementary material, which is available to authorized users.
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Feng G, Long Y, Peng J, Li Q, Cui Z. Transcriptomic characterization of the dorsal lobes after hepatectomy of the ventral lobe in zebrafish. BMC Genomics 2015; 16:979. [PMID: 26584608 PMCID: PMC4653908 DOI: 10.1186/s12864-015-2145-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 10/26/2015] [Indexed: 02/08/2023] Open
Abstract
Background The liver possesses an ability of compensatory growth after removing three of five lobes in mammals or one of three lobes in zebrafish. The reenter of hepatocytes into the cell cycle is one of the hallmarks for the initiation of liver compensatory growth, but cellular and molecular mechanisms underlying the activation of hepatocytes remain largely unknown. Results To better understand the process, transcriptional profiles of the remaining liver dorsal lobes in female zebrafish were generated with RNA-seq. About 44 million raw reads were obtained from three sequencing libraries and 71 % of raw reads were mapped to the reference genome of zebrafish. A total number of 5652 genes were differentially expressed in at least one of two time points during the compensatory growth of liver dorsal lobes and classified into different functional categories. A number of genes encoding angiogenesis-related growth factors/ligands and apoptosis-associated cytokines were strongly expressed at 6-h time point after the removal of the ventral lobe. Gene ontology enrichment analysis of genes up-regulated during early stages of liver compensatory growth revealed that small GTPase-mediated signal transduction, RNA processing and intracellular protein transport were the most highly overrepresented biological processes and SNARE interactions in vesicular transport, proteasome and basal transcription factors were the most highly enriched pathways. Moreover, 477 genes differently expressed during liver compensatory growth of both female zebrafish and mice were involved in the response to stimulus, DNA replication, metabolic processes of fatty acid, lipid and steroid, multicellular organismal homeostasis and extracellular matrix constituent secretion. Conclusions Multiple biological processes and signaling pathways are immediately activated in remaining dorsal lobes of female zebrafish right after removal of the ventral lobe and these findings provide crucial clues for further identification of cis-elements and trans-factors that are extensively involved in the initiation of liver compensatory growth. Electronic supplementary material The online version of this article (doi:10.1186/s12864-015-2145-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Guohui Feng
- The Key Laboratory of Aquatic Biodiversity and Conservation of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, Hubei, China. .,University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Yong Long
- The Key Laboratory of Aquatic Biodiversity and Conservation of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, Hubei, China.
| | - Jinrong Peng
- Zhejiang University, Hangzhou, 310058, Zhejiang, China.
| | - Qing Li
- The Key Laboratory of Aquatic Biodiversity and Conservation of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, Hubei, China.
| | - Zongbin Cui
- The Key Laboratory of Aquatic Biodiversity and Conservation of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, Hubei, China.
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